ArticleScientific reports2026
Contribution of cytochrome P450-mediated metabolism to clavulanic acid-induced cytotoxicity in TK6-derived cytochrome P450-overexpressing cell lines.
Article in Scientific reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Clavulanic acid, a β-lactamase inhibitor, is widely co-administered with amoxicillin (as in Augmentin) to treat a broad range of mild-to-moderate bacterial infections by inhibiting β-lactamase enzymes produced by resistant bacterial strains. Despite its therapeutic efficacy, clavulanic acid has been associated with drug-induced liver injury, but the underlying mechanisms for this toxicity remain poorly understood. We investigated the contribution of cytochrome P450 (CYP)-mediated metabolism in relation to clavulanic acid-induced cytotoxicity. A panel of TK6-derived cell lines overexpressing 18 individual CYP isoforms (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP4A11, and CYP4B1) was employed. Cells were incubated for 24 and 48 h with freshly prepared clavulanic acid (20-1000 µM) in RPMI-1640 medium, and the half-maximal inhibitory concentration (IC₅₀) was determined. Cell growth was more markedly delayed after 48 h of treatment than after 24 h of exposure. Following 48 h of treatment, 13 CYP-overexpressing cell lines showed reduced IC₅₀ values compared with parental TK6 and TK6/vector control cells. The rank order was CYP3A4 ≈ CYP3A7 ≈ CYP1A1 < CYP4A11 ≈ CYP2A13 ≈ CYP2C19 < CYP2B6 ≈ CYP1A2 ≈ CYP2C9 < CYP1B1 ≈ CYP2D6 < CYP2E1 ≈ CYP2C18, with the greatest decrease (~2-fold) observed in TK6/CYP3A4 cells. In contrast, five isoforms (CYP2A6, CYP2A7, CYP2C8, CYP3A5, and CYP4B1) showed IC₅₀ values comparable to controls. To examine further the cytotoxic response, TK6/CYP vector and TK6/CYP3A4 cells were treated for 48 h with equitoxic concentrations of clavulanic acid (0.1×, 0.5×, and 1.0× IC₅₀). The exposures resulted in a significant concentration-dependent reduction in cell viability, accompanied by increased lactate dehydrogenase release, the induction of apoptosis, G₀/G₁ phase arrest, and a concentration-dependent elevation in γH2AX phosphorylation, indicative of DNA damage. In conclusion, CYP enzymes, especially CYP3A4, likely contribute to clavulanate-induced cytotoxicity, with necrosis, cell cycle disruption, and γH2AX-associated apoptosis as key cellular responses.
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